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A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.
Greenway, FL, Aronne, LJ, Raben, A, Astrup, A, Apovian, CM, Hill, JO, Kaplan, LM, Fujioka, K, Matejkova, E, Svacina, S, et al
Obesity (Silver Spring, Md.). 2019;(2):205-216
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Abstract
OBJECTIVE This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. RESULTS Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.
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Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.
van der Kolk, BW, Kalafati, M, Adriaens, M, van Greevenbroek, MMJ, Vogelzangs, N, Saris, WHM, Astrup, A, Valsesia, A, Langin, D, van der Kallen, CJH, et al
Diabetes. 2019;(12):2247-2258
Abstract
Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.
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Long-term weight-loss maintenance in obese patients with knee osteoarthritis: a randomized trial.
Christensen, P, Henriksen, M, Bartels, EM, Leeds, AR, Meinert Larsen, T, Gudbergsen, H, Riecke, BF, Astrup, A, Heitmann, BL, Boesen, M, et al
The American journal of clinical nutrition. 2017;(3):755-763
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Abstract
Background: A formula low-energy diet (LED) reduces weight effectively in obese patients with knee osteoarthritis, but the role of LED in long-term weight-loss maintenance is unclear.Objective: We aimed to determine the effect of intermittent LED compared with daily meal replacements on weight-loss maintenance and number of knee replacements over 3 y.Design: The design was a randomized trial with participants aged >50 y who had knee osteoarthritis and a body mass index [BMI (in kg/m2)] ≥30. Participants were recruited from the osteoarthritis outpatient clinic at Copenhagen University Hospital in Frederiksberg, Denmark; they had previously completed a 68-wk lifestyle intervention trial and achieved an average weight loss of 10.5 kg (10% of initial body weight). Participants were randomly assigned to either the intermittent treatment (IN) group with LED for 5 wk every 4 mo for 3 y or to daily meal replacements of 1-2 meals for 3 y [regular (RE) group]. Attention by dietitians and the amount of formula products were similar. Primary outcomes were changes in body weight and proportion of participants receiving knee replacements. Outcomes were analyzed on the intention-to-treat-population with the use of baseline-carried-forward imputation for missing data.Results: A total of 153 participants (means ± SDs: BMI: 33.3 ± 4.6; age: 63.8 ± 6.3 y; 83% women) were recruited between June and December 2009 and randomly assigned to the IN (n = 76) or RE (n = 77) group. A total of 53 and 56 participants, respectively, completed the trial. Weight increased by 0.68 and 1.75 kg in the IN and RE groups, respectively (mean difference: -1.06 kg; 95% CI: -2.75, 0.63 kg; P = 0.22). Alloplasty rates were low and did not differ (IN group: 8 of 76 participants; RE group: 12 of 77 participants; P = 0.35).Conclusions: After a mean 10% weight-loss and 1-y maintenance, additional use of daily meal replacements or intermittent LED resulted in weight-loss maintenance for 3 y. These results challenge the commonly held assumption that weight regain in the long term is inevitable. This trial was registered at clinicaltrials.gov as NCT00938808.
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Comparison of results from different imputation techniques for missing data from an anti-obesity drug trial.
Jørgensen, AW, Lundstrøm, LH, Wetterslev, J, Astrup, A, Gøtzsche, PC
PloS one. 2014;(11):e111964
Abstract
BACKGROUND In randomised trials of medical interventions, the most reliable analysis follows the intention-to-treat (ITT) principle. However, the ITT analysis requires that missing outcome data have to be imputed. Different imputation techniques may give different results and some may lead to bias. In anti-obesity drug trials, many data are usually missing, and the most used imputation method is last observation carried forward (LOCF). LOCF is generally considered conservative, but there are more reliable methods such as multiple imputation (MI). OBJECTIVES To compare four different methods of handling missing data in a 60-week placebo controlled anti-obesity drug trial on topiramate. METHODS We compared an analysis of complete cases with datasets where missing body weight measurements had been replaced using three different imputation methods: LOCF, baseline carried forward (BOCF) and MI. RESULTS 561 participants were randomised. Compared to placebo, there was a significantly greater weight loss with topiramate in all analyses: 9.5 kg (SE 1.17) in the complete case analysis (N = 86), 6.8 kg (SE 0.66) using LOCF (N = 561), 6.4 kg (SE 0.90) using MI (N = 561) and 1.5 kg (SE 0.28) using BOCF (N = 561). CONCLUSIONS The different imputation methods gave very different results. Contrary to widely stated claims, LOCF did not produce a conservative (i.e., lower) efficacy estimate compared to MI. Also, LOCF had a lower SE than MI.
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Impact of weight loss and maintenance with ad libitum diets varying in protein and glycemic index content on metabolic syndrome.
Papadaki, A, Linardakis, M, Plada, M, Larsen, TM, Damsgaard, CT, van Baak, MA, Jebb, S, Pfeiffer, AF, Martinez, JA, Handjieva-Darlenska, T, et al
Nutrition (Burbank, Los Angeles County, Calif.). 2014;(4):410-7
Abstract
OBJECTIVES We investigated the effects of weight loss and maintenance with diets that varied with regard to protein content and glycemic index (GI) on metabolic syndrome (MetSyn) status. METHODS Secondary analyses were performed within the Diet, Obesity and Genes (DiOGenes) study (2006-2008), a randomized controlled dietary intervention. Nine hundred and thirty-eight overweight and obese adults from eight European countries entered an 8-wk low-calorie-diet period. Seven hundred and seventy-three adults who lost at least 8% of their body weights were randomized to one of five ad libitum diets for 6 mo: 1) low-protein (LP)/low-GI (LGI); 2) LP/high-GI (HGI); 3) high-protein (HP)/LGI; 4) HP/HGI; and 5) control diet. MetSyn prevalence and a standardized MetSyn score were assessed at baseline, after the low-calorie diet, and after the intervention. RESULTS Weight loss among participants while on the low-calorie diet significantly reduced MetSyn prevalence (33.9% versus 15.9%; P < 0.001) and MetSyn score (-1.48 versus -4.45; P < 0.001). During weight maintenance, significant changes in MetSyn score were observed between the groups, with the highest increase detected in the LP/HGI group (P = 0.039, partial η(2) = 0.023). Protein, GI, and their interaction did not have isolated effects on study outcomes. CONCLUSIONS Neither protein nor GI affected MetSyn status in this sample of European overweight and obese adults. However, a diet with a combination of an increased protein-to-carbohydrate ratio with low-GI foods had beneficial effects on MetSyn factors.
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The effectiveness of breakfast recommendations on weight loss: a randomized controlled trial.
Dhurandhar, EJ, Dawson, J, Alcorn, A, Larsen, LH, Thomas, EA, Cardel, M, Bourland, AC, Astrup, A, St-Onge, MP, Hill, JO, et al
The American journal of clinical nutrition. 2014;(2):507-13
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Abstract
BACKGROUND Breakfast is associated with lower body weight in observational studies. Public health authorities commonly recommend breakfast consumption to reduce obesity, but the effectiveness of adopting these recommendations for reducing body weight is unknown. OBJECTIVE We tested the relative effectiveness of a recommendation to eat or skip breakfast on weight loss in adults trying to lose weight in a free-living setting. DESIGN We conducted a multisite, 16-wk, 3-parallel-arm randomized controlled trial in otherwise healthy overweight and obese adults [body mass index (in kg/m²) between 25 and 40] aged 20-65 y. Our primary outcome was weight change. We compared weight change in a control group with weight loss in experimental groups told to eat breakfast or to skip breakfast [no breakfast (NB)]. Randomization was stratified by prerandomization breakfast eating habits. A total of 309 participants were randomly assigned. RESULTS A total of 283 of the 309 participants who were randomly assigned completed the intervention. Treatment assignment did not have a significant effect on weight loss, and there was no interaction between initial breakfast eating status and treatment. Among skippers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.71 ± 1.16, -0.76 ± 1.26, and -0.61 ± 1.18 kg for the control, breakfast, and NB groups, respectively. Among breakfast consumers, mean (±SD) baseline weight-, age-, sex-, site-, and race-adjusted weight changes were -0.53 ± 1.16, -0.59 ± 1.06, and -0.71 ± 1.17 kg for the control, breakfast, and NB groups, respectively. Self-reported compliance with the recommendation was 93.6% for the breakfast group and 92.4% for the NB group. CONCLUSIONS A recommendation to eat or skip breakfast for weight loss was effective at changing self-reported breakfast eating habits, but contrary to widely espoused views this had no discernable effect on weight loss in free-living adults who were attempting to lose weight.
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Experience and acceptability of diets of varying protein content and glycemic index in an obese cohort: results from the Diogenes trial.
McConnon, A, Horgan, GW, Lawton, C, Stubbs, J, Shepherd, R, Astrup, A, Handjieva-Darlenska, T, Kunešová, M, Larsen, TM, Lindroos, AK, et al
European journal of clinical nutrition. 2013;(9):990-5
Abstract
BACKGROUND/OBJECTIVES To investigate acceptability and tolerability of diets of different protein and glycemic index (GI) content aimed at weight maintenance following a phase of rapid weight loss, as part of a large pan-European dietary intervention trial. SUBJECTS/METHODS The Diogenes study (www.diogenes-eu.org) consisted of an initial 8-week rapid weight-loss phase (800-1000 kcal/day), followed by a 6-month weight maintenance intervention with five different diets varying in protein and GI content. Measurement of a range of outcomes relating to experience of the Diogenes diets in terms of acceptability, experience and mood were recorded via end of day questionnaires throughout the study. RESULTS Weight change during the initial weight loss phase weakly, but positively correlated with acceptability of the programme (r range=-0.08 to 0.2, P 0.05, n=685 on four of five dimensions). Success at weight maintenance positively correlated with acceptance of the programme (r range=-0.21 to -0.34, P<0.001, n=540 for all five dimensions). The diets with higher protein content were more acceptable than the low protein (LP) diets, however, no differences between the high vs low GI diets were found concerning acceptability and tolerability. CONCLUSIONS Results suggest that moderately high protein diets, compared with LP diets, are more acceptable diets for weight control in overweight individuals.
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Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men.
Wang, P, Holst, C, Wodzig, WK, Andersen, MR, Astrup, A, van Baak, MA, Larsen, TM, Jebb, SA, Kafatos, A, Pfeiffer, AF, et al
International journal of obesity (2005). 2012;(12):1545-51
Abstract
BACKGROUND Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project. OBJECTIVE To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women. DESIGN Subjects, who lost ≥ 8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months. SUBJECTS 125 overweight/obese healthy men from eight European countries who completed whole intervention. MEASUREMENTS Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters. RESULTS Serum ACE concentration decreased by 11.3 ± 10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain ≤ 20% after 6 months, with an odds ratio of 1.59 (95% confidence interval (CI): 1.09-2.33, P=0.016) for every 10% reduction, which was independent of body mass index and weight loss. The prediction power was weaker in men than in women, but without a significant sex difference (P=0.137). In pooled subjects (N=218), the odds ratio was 1.96 (95% CI: 1.46-2.64, P<0.001). CONCLUSIONS A greater reduction of ACE during weight loss is favorable for weight maintenance in both men and women. This can offer useful information for personalized advice to improve weight loss maintenance. It also confirms the role of ACE in the metabolic pathways of weight regulation.
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Clinical correlates of weight loss and attrition during a 10-week dietary intervention study: results from the NUGENOB project.
Handjieva-Darlenska, T, Holst, C, Grau, K, Blaak, E, Martinez, JA, Oppert, JM, Taylor, MA, Sørensen, TI, Astrup, A
Obesity facts. 2012;(6):928-36
Abstract
OBJECTIVE The aim of this study was to identify the pre-treatment subject characteristics and weight loss changes as determinants of weight loss and attrition during a 10-week dietary intervention study. METHODS A total of 771 obese subjects (BMI 35.6 kg/m(2)) of both genders were included from 8 clinical centres in 7 European countries, who underwent a 10-week dietary intervention study comparing two hypo-energetic (-600 kcal/day) diets varying in fat content. RESULTS The multiple regression model showed that weight loss at week 10 was predicted by: 6.55 + 1.27 × early weight loss (kg) at week 1 + 1.35 × gender (R(2) = 0.28, p < 0.001). When performing the corresponding model with half-way weight loss (week 5) as covariate, the regression equation was: weight loss (kg) at week 10 = 1.88 + 1.38 × half-way weight loss (kg) (week 5) + 0.42 × gender (R(2) = 0.77, p < 0.001). A cut-off target of ≥ 4 kg weight loss at week 5 emerged as an optimal predictor for reaching at least 10% weight loss at week 10. Greater attrition likelihood was predicted by high-fat diet, decreased early and half-way weight losses. CONCLUSION Early and half-way weight losses are associated with and could contribute to prediction of the final weight loss and attrition.
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The effect of tesofensine on appetite sensations.
Gilbert, JA, Gasteyger, C, Raben, A, Meier, DH, Astrup, A, Sjödin, A
Obesity (Silver Spring, Md.). 2012;(3):553-61
Abstract
Tesofensine (TE), an inhibitor of monoamine presynaptic reuptake, has produced twice the weight loss seen with currently marketed drugs. However, its long term effect on appetite in humans has not been studied. A multicentre phase II trial was divided into two parts (24 weeks each). Part 1 had a randomized, double-blind, placebo-controlled design and Part 2, an open-labeled, single-group, uncontrolled design. A drug-free period (12 ± 3 weeks) separated them. In Part 1, participants (n = 158) were assigned to 0.25, 0.5 or 1.0 mg TE, or placebo. Completers of Part 1 were invited to participate in Part 2 (n = 113), during which they all received 0.5 or 1.0 mg TE. Appetite sensations and a composite satiety score (CSS = satiety + fullness + (100 - hunger) + (100 - prospective food consumption) were assessed. In Part 1 TE induced a dose-dependent increase in CSS at week 12 that correlated with weight loss during the 24 weeks (r = 0.36, P < 0.0001). However, CSS diminished over time as weight loss progressed (e.g., for 1.0 mg; 52 ± 17 mm; 64 ± 13 mm; 55 ± 13 mm at baseline, week 12 and week 24, respectively). After drug withdrawal CSS returned to baseline values (50 ± 17 mm, in the whole sample.), despite the participants' reduced-weight state (-7.2 ± 6.7 kg, P < 0.0001). The reintroduction of TE in Part 2 increased CSS again (56 ± 17 mm at week 60), regardless of initial treatment/weight loss. We postulate that enhanced satiety is involved in early weight loss. Whether the attenuated effect on appetite seen after 24 weeks is due to a counteracting effect in the weight reduced state or whether the appetite suppressing effect of TE per se diminishes over time is, however, still unclear.